Ann: GBM Agile Update, page-101

A significantly improved PFS does not provide what would normally be regarded as adequate evidence of clinical utility.

However, in the case GBM, KZA may seek approval from the regulators based on an improved PFS, particularly, given temozolomide has no activity 2/3 of GBM patients. These patients essentially represent an unmet medical need.

Finally, should a large enough trend toward improved OS with paxalisib be demonstrated relative to the control arm, KZA may be successful in obtaining approval from the regulators.

As with PFS, a trend toward improved OS would normally be regarded as inadequate evidence of clinical utility, but we are still talking about a group of patients that have run out of options.

In the latter two cases (improved PFS, strong OS trend), it is likely that the regulators would grant KZA an accelerated approval for GBM, allowing the drug to be sold on market.

The catch is that it would be highly likely that they would require KZA to perform a confirmatory phase III trial even while the drug was already being sold. If the trial were to fail the regulator may remove the drug from the market, although, in practice, this tends not to be the case.

We imagine that many investors may well be thinking, no, this is the end of paxalisib in GBM. However, it easy to find examples where drugs have been approved for diseases that have proven to be particularly hard treat without demonstrating a significant improvement in an approvable endpoint over a control arm and, sometimes, even when there is no control arm.

For example:

• Exondys 51 (eteplirsen) was developed by Sarepta Therapeutics for the very severe muscle wasting disease Duchenne muscular dystrophy, which leads to very significant morbidity and early death. Exondys 51 was given an accelerated approval in 2016 by the FDA based on a surrogate endpoint (an endpoint that does not demonstrate any direct clinical benefit to the patient) in a single arm study (i.e., no control arm) comprising only 12 evaluable patients. As part of the accelerated approval, the FDA required Sarepta to run a more definitive as part of the accelerated approval process, even though the drug was already being sold on market. However, Sarepta has not yet completed that trial even though they have had six years to do so.


very interesting information - we have had 30 patients + GBM Agile stage 1 of maybe 150 as it was fully recruited though not moving to stage 2 and we did offer a life extension and in 60% more patients than the current standard of care…

all of these leads me to believe our case for an approval is far far stronger than than this example or the others on the report

A Pax Approval in GBM is far from finished May we’ll be the quickest path to approval yet.